Method of preparation of cyclopentanophenanthrene derivatives



United States Patcrit O METHOD OF PREPARATION OF CYCLOPENTA- NOPHENANTHRENE DERIVATEVES George Rosenkranz, Mexico City, Mexico, and Carl Djerassi, Birmingham, Mich., assignors, by mesne assignments, to Syntex, S. A., Mexico City, Mexico, a:

corporation of Mexico Claims priority, application Mexico February 19, 1952 35 Claims. (Cl. 260-23955) The present invention relates to novel cyclopentanophenanthrene derivatives and to a novel method for the preparation thereof.

More particularly, the present invention relates to the preparation of lla-hydroxy steroidal sapogenin derivatives having the Ring A structure characteristic of diosgenin, as well as for the preparation of certain novel intermediates.

Diosgenin (A -22-isospirosten-3B-ol) is a desirable starting material for the manufacture of sexual hormones and has so been utilized for some time since the Ring A structure thereof may be readily converted to the 3-keto A structure characterizing a great many hormones and the sapogenin side chain may be readily degraded to the side chain characterizing compounds of the pregnane series which may thereafter be converted to the various side chains characterizing the hormones. Considerable difliculty, however, has been found in producing cortical hormones which are oxygenated in Ring llDetlon" or. Deiodinatton Patented June 24, 1958 C from diosgenin and an ideal starting material would be a 'sapogenin which containedsuch an oxygen func-' tion at position 11 of the molecule as well as the functional groups present in the molecule of diosgenin. Sapogenins of this' type, however, are heretofore unknown.

In accordance with the present invention, therefore,

there has been discovered a novel method for producing 11cc hydroxy derivatives having a sapogenin side chain and the Ring A structure characteristic of diosgenin.

. It has further been discovered in accordance with the present invention'that these novel compounds may be I ,prepared from 22-isoallospirostan-3p,1la-diol diacetate disclosed in United States patent application Serial Number 291,555, now Patent No. 2,712,027.

The novel final compounds of the present invention, as for example A -22-isospirosten-3p,1la-diol and/0r esters thereof are important intermediates for the pro .duction of cortical hormones having ll-oxy substituents. For example, A -22-isospirosten-3p,llot-diol diacetate may be ,oxidatively degraded by known methods utilized for the degradation of the sapogenin side chain to A pregnadien-SpJlea-diol-ZO-one diacetate. The, 16-double bond may then be selectively saturated by hydrogenation in the presence of a palladium catalyst and the A -diester saponified to the free diol. Dibromination of the resultant A -pregnen-3fi,11adiol-20 one followed by treatment with sodium iodide, followed by treatment with sodium acetate produces A pregnen-3fi,1la,2l-triol-20-0ne 21 monoacetate. Openauer oxidation of this last compound produces A -pregnen-11 a,21-diol-3,20dione, 21 acetate. Oxidation, with chromic acid of the llot-hydroxy group thenproduces the known compound ,ll-dehydro. corticosterone acetate. 7

The process of the present invention may be exemplified by the following equation:

' Partial Saponldcatlon Fallowed by Oxidation Sodium ma Aeetylating Agent Acid Catalyst In the above equation Rrepresents an acyl group, i. ,e. the residue of any organic acid customarily utilized for the esterification of steroid alcohols, preferably R represents the residue of the 'lowerfatty acid such as acetic or propionic or the residue of anaromatic acidsuch as benzoic. In the aboye, equation, further, R represents the same acid residues as hereinbefore set forth and in addition may represent hydrogen. Ac represents the acetyljradical. q

In practicing the diester, as for example the; diacetatej of 22-isoallospirostan-3/3,1la-diol, is treated with approximately one molar equivalent of a mild saponifying agent, as for example an alkalimetal bicarbonate, to prepare ,the corresponding 11=mono ester, as, for example. the ,1: l-mono acetate. This ll-mono acetate Can'the'n be oxidized, as for example with chromic acid N-bromoacetarnide or with an aluminum alkoxide in the presence of a hydrogen acceptor, to produce the corresponding ll-mono ester of 22-isoallospirostan-1la-ol-S-one.

Before proceeding with the next step of the process, i. e. the polybromination, the mono ester may be saponified process above outlined a suitable i Reduction With Sod ium Borohydride Followed by Est to produce the free- 22-isoallospirostan-1la-ol-S-one. For a 4 the polybromination, the free compound or the ester is treated with bromine in acetic acid in the presence of a isoallospirostan-l 1oz-0l-3-OI!O ester or free compound whichis thus obtained can then be treated with sodium iodide in a ketone solvent in order to prepare the corresponding 2iod0-23-bromo-A -22-isospirosten-11a-ol-3-one esteror the corresponding free compound. The 2-iodo- A compound thus produced can then either be completely dehalogenated, ortdeiodinated. For the dehalogenation, a suitableagent is zinc in alcohol solution and the resulta'nt compound is, for example A -22-isospirosten-1la-ol-3-one acetate. In this'particularcase the X represents hydrogen.

few drops of hydrobromicacid. The 2,4,23-tribromo-22- In the alternative, instead of complete dehalogenation one'acetatemay be deiodinated; For this purpose, reducing agents such as chromous chloride, collidine' di'rnethylthe 2 iodo 23 lbromo A 22 isospirosten l1oc-Q1-3- aniline or sodium bisulfite may beutilized. Other tertiary amines may also be used: The 23-bromo derivative thus produced maythen be debrominated by treatment with zinc, or it maybe utilized as such for the next step of the:

present process. In the case where the compound is,

erification its 23-bromo derivative and then be treated with a suitable acetylating agent such as isopropenyl acetate or acetic'anhydride in the presence of an acid catalyst to form the.

corresponding enol acetate. Finally, the. enol. acetatecan be treated with sodium borohydride toproduce the .de-

sired A -22j-isospirosten-3/i1lwdiol, which is preferably,"

esterified in situ to produce the corresponding 3,11 diester. Where the 23 -bromo derivative is utilized, as will be understood, the corresponding 23-bromo-A -22-isospirosten- 3B,11a-diol and/or its ester is preparedi The 23-bromo derivative can then be dehalogenated by reductio n with zinc as indicated in the following equation: a p

Although in the above equations and descriptions, as well as "the examples which follow, the invention is illustrated with examples taken from the 22-iso series, the present invention can also be applied to the corresponding sapogenins with the normal configuration at C-22. The only difierence in the case of bromination of the (1-22 normal sapogenins is that an additional mol of bromine is required since these sapogenins form 23,23-

d'ibromo derivativesand in each case where various bromo derivatives are described in the present specification, it will be understood that where the C-22 normal s'apogenins are referred to that anadditional mol of bromine is present at C-23. i

The following specific examples serve to illustrate but are not intended to limit the present invention:

Example I A An alcoholic solution of 22-isoallospirostan-3B,l lob-diol diacetate was refluxed for 30 minutes with an aqueous solution of 1.1 molar equivalents of sodium bicarbonate (potassium bicarbonate can also be used), The mixture was poured into water and the precipitate was collected, washed to neutral, dried in air and recrystallized from methanol to yield 22-isoallospirostan- 3p,ll t-diol llmonoacetate.

Example II Example III 1 g. of 22-isoallospirostan3fl,1lot-diol ll-monoacetate was dissolved in a mixture of 140 cc. of toluene and cc. of cyclohexanone and 40 cc; of the mixture were distilled in order to remove traces of moisture. To the boiling solution it was added a solution of 1.20 g. of-aluminum isopropylate in 50 cc. of anhydrous toluene in the course of 45 minutes, maintaining a slow distillation during all this time. cc. of a concentrate'd solution of sodium-potassium tartrate were added to the cooled solution and the mixture was subjected to steam distillation for removal of the volatile components. The mixture was extracted with ether and the ether solution was washed Example IV 440 mg. of N- bromoacetamide were added in small porinto the more stable 2,4-dib ro mo configuratiom'iift: poured into water and the precipitate was filtered'and washed with water. 2,4,23-tribromo-ZZ-isoallospirostanlla-ol-3-one acetate was thus'obtained; V f

Example VI A solution of 5.2 gfof 2,4,23-tribromo22 isha llospirostan-11a-ol-3-one acetate, such asobta'ined, according to the previous example, and 18 g. ofsodium iodide'in 500 cc. of acetone was refluxed during 3 hours and then kept standing at room temperature during 72 hours. The solution was diluted with ether and washed with water, sodium thiosulfate solution, sodium bicarbonate and water, dried over sodiumsulfate and evaporated to dryness. 2 iodo 23-bromo-A -22-isospirosten-1-la-ol-3- one acetate was thus obtained which showed an ultraviolet absorption maximum at 237 my (log 6 4.25) and was used without further purification for the next experiment.

Example VII A solution of'4.1 g. of 2-iodo-23 bromo-A -22-isospirosten-11wo1-3-one in 1500 cc.,of alcohol was refluxed with 80 g. of zinc dust during5 hours. The solution was filtered and theresidual zinc was well washed with ether. The combined filtrateswere washed with water,

dried over sodium sulfate and evaporated to drynes's.=

Crystallization of the residue-from chloroform-methanol yielded A -22 isospirosten-1lot-ol 3-one acetate with an ultraviolet absorption maximum at 238 m,w(log e 4.28)."

Saponification of the above acetate with 5% methanolic potassium hydroxide (sodium hydroxide can be used in-.

stead) refluxing thesolution during one hour under an atmosphere of nitrogen afforded the free A -22-isospirosten-l1wol-3-one. I

Example VIII and Djerassi, J. Am. Chem. Soc., 72, 4077 (1950). After 15 minutes, the solution was poured into water, extracted with ether, washed with sodium bicarbonate and water, dried and concentrated to a small volume until crystallization started. The precipitate was-filtered, yielding 23- tions to a solutionof l g. of 22-isoallospirostan-3fi,l1a-

diol ll-mono acetate in 25 cc. of pyridine maintaining the temperature at 20 during the operation. After standing overnight at room temperature, the solution was dilutedv with water and extracted withether. ,The ether layer was repeatedly washed with dilute hydrochloric acid and then with sodium bicarbonate and water, dried over sodium sul- Example V.

Example V A solution of 5.6 g. of 22-isoallospirostan-11a-ol-3 one acetate in 170 cc. of glacial acetic acid was mixed with 8 drops of a 4-normal solution of hydrobromic acid in acetic acid and the mixture was treated with a solution of 7.4 g. of bromine in 75 cc. of acetic acid which was added dropwise' under continuousstirring and maintain ing the temperature of the solution at 22 C. -After keeping the mixture. overnight at room temperature in bromo-N-isospirosten-l1u-ol-3-one acetate with anultraviolet absorption maximum at 238 m (log a 4.28).

ExampleIX A solution of 1 g. of M-ZZ-isospirosten-lla ol-3-one acetate in 60 cc. of benzene was treated with .150 mg. of p-toluenesulfonic acid and 4 cc. of isopropenyl acetate (the free A -22-isospirosten-1lozeol-3-one can ,be used in-- stead of the acetate, yielding the same result). The solution was slowly concentrated in the course of 5 hours to a final volume of 15 cc.; 4 cc. more of isopropenyl acetate were added at the end of the first hour and 2 cc. more at the end of the second and third hours. .The

,mixture was concentrated to dryness under 1 vacuum', di-

luted with ether and washed'with water,.sodium bicarbonate and water, dried and evaporated todryness. The

order to complete the rearrangement of the 2,2-dibromo 715 residue crystallized from a ixt o et e e identical .to the one described "7 to which one drop-of pyridine had been added. A -22- isospirostadien-Lll -diol diacetate was thus obtained, with an ultraviolet absorption maximum at 235 mp. (log e 4.05). The infrared:spectrum,.;determined in chloroterm solution, showed a maximum at 1736 cm.- (acetate) and showed no band of ego-unsaturated keto groups.

Thesame reaction carried outy on the corresponding 23-broi no. derivative gave in this case .23-bromo-A -22-. isospirostadien 3,l'la-diolfdiacetate with the same physical characteristicsas the ehol acetate .described above.

Earample fXl 51mph. X11 1 l g. of A -ZZ isospimstadien-SJlot-die] diacetate was dissolved in-40 cc. of dioxane and 60 cc. of methanol. The solution was cooled in ieeand treated with a solu tion 051:6 goof sodium borohydride in40 cc. of'methanol and 3 cc. of water -whieh was' added inone portion. The mixture was kept. overnight 'at atemperature of 10 C. and thenheated during- 30 minutes atthe temperature of the steam bath. It'wasdi1uted with water and extracted with chloroform; washed, dried over sodium sulfate" and evaporated to dryness. Theresiduewas directlyacetylated with pyridine and acetic anhydrideto give A -"22-isospiro'stenfldle-diol diacetatei This substance showed no selective absorption in the ultraviolet spectrumand in the infrared it had a band at 1736 cmJ-Ldypichloface tates, and had no band of free hydroxy groups.

Saponification of this compound by refluxing with 5% methanolic sodil r rl" (br.lpotassium) hydroxide'gave the free'A 22 isospirosten 3ml1ix diol. p

The samercactionjcarried out with the corresponding 23-bromo derivative gav'e1in thiscasethe corresponding 23:hromo-a 22 isospirosten 3p;1l t-diol. v

i Example XIII l A is olution ofj of 23 bromo-d 22-isospirostenw during. 8 hourswith. l2 gppf zinc dust. The solution was lized from acetonehexane, to ;give .Ai-ZZ-ismpirosten; 3fl,lla-Cll0l diacetate identical to the compound obtained according to Example XII.

Weclaim:

"115 A 'piocess for; the; production of an jl'l mono ester orananqs tostan-llmol one which comprises treating a corresponding diester of "an allospiros tan-lldl l mdiol with a molar equivalelri t' o'fa mildsapon i fying agent to produce the corresponding 11] mono ester and oxidizing said ll-mono estef with an oxidizing" agent selected from the group consisting of chromic acid, N-bromoacetami'de and an aluminum alkox isle in the presence ot-a hydrogen acceptor. p l 1 *2: in process "for the redecessor; 22-isoallos'pirosta'nl'la-ol-3-on'e Y acetatefwh 'ch comprises treating" f 22 -is'o' allospirosta'n' 3fl 1ld5diol diacetate with l'sodiurnf" hicar bonatvtorpaitiallyfsaponifythefsame and produce the corresponding 11 nionoacetate and oxidizing said '11 mono acetatean oxidizing" agent selected from'the group consisting of "chromic acid -bromoacetamide and an aluminum lkoxide the presence of a'hydrogcn' ac apt V 7 Fig. 1 r

-3. A wprocess- -for the 'producti'on of 23 *b rorninatedestersor 2-iodo A- -"spi summers-ans which comprises polyhrominatinga'reorresponding ester of anallospirostan-lr1a-ol+B-.ohe to. give the-corresponding 2,4}23

7 ing ofI 2,4,23polybromo-allospirostan-lld -ol-3-one and polybromo derivative and thereafter treating said polybromo derivative with sodium iodide.

4. A process for the production of 2-iodo-23-bromo- A -22-isospirosten-11u-ol-3-one acetate which comprises polybrominating 22isoallospirostan-lla-0l-3-one acetate to give the corresponding 2,4,23-tribromo compound and reacting said tribr omo compound with sodium iodide.

5. A process for the production of esters of 21 A spirosten-lld-ol-S-one compound which comprises reducing with zinc a corresponding 23 brominated ester of a 2-iodo-A -spirosten-l1a-ol-3-one compound.

6. The process of claim 5 wherein the product is A -22-isospirosten-1lot-ol-3-one acetate and the starting material is 2-iodo- 23-bro1no-A -22-isoallospirostcn-1laol- 3 -one acetate.

7. A process for the production of a 23 brominatcd ester of M-spirosten-lla ol-3-one, which comprises treating a corresponding 23 brominated ester of 2-iodo-A spirosten-1la-ol-3-one with a reducing agent selected from the class consisting of chromous chloride, at tertiary amine and sodium sulfite.

8. The process of claim 7 wherein the product is 23- bromo-M-ZZ-isospirosten-1loc-ol-3-one acetate and the starting compound is 2-iodo-3-hromo-A -22-isospirosten- 11a-ol-3-one acetate.

9. A process for the production of a compound selected from the class consisting of a. 3-acetoxy-11aacy1oxy-A -spirostadien compound, a 3,11a-diacetoxy- A -spirostadien compound and 23 brominated deriv tives thereof which comprises treating the corresponding compound selected respectively from the class consisting of an ester of a a -spirosten l1ot-ol-3-one, a A spirostcn- L-Ol-3-Ol1e, and its 23 bromo derivatives with an acetylating agent in the presence of an acid catalyst.

10. The process of claim 9 wherein the acctylating agent is selected from theclass consisting of isopropenyl acetate and acetic anhydride.

11. A process for the production of a diestcr selected from the class consisting of diesters of A -Spirosten- 3fl,lloc-Cli0l and 23 bromo derivatives thereof, which comprises treating a compound selected from the class consisting of 3-acetoxy-lla-acyloxy-A -spirostadien and 23 brominated derivatives thereof with sodium borohydride followed by esterification.

12.. The processof claim 11 wherein the product is A -22-isospirosten-3/3,1lardiol diacetate and the starting compound is A -22-isospirostadienr3,1la-diol diacetate and .the 'esterification is an: acetylation.

13. The process of claim. 12 wherein the product is 23-bromo A5-22-isospirosten-3d,1Ia-diol diacetate and the.

starting compound is 23-bromo-A -22-isospirostadien- 3,11a-dl0l diacetate and the esterification is an acetylation Mall-mono esters of. an allospirostan-3fl,lle-diol.

. 15..f22{isoallospirostan-3,3,1lot-diol ll-mono acetate.

16.: IA new compound selected from the group con sisting of allospirostan-ll t-ol 3-one and esters thereof.

. 17. Anew compound selected from the .class consisting,of 22-isoallospirostand1a-0l-3-one and esters thereof.

'18. 'Allospirostan-lla ol-3-one acetate. i 19 Allospirostan-lla ol-3-one.

2 0aA-new compound selected from the class consistestersthereof. p m

21. 2,4,23 F tribrorno 22-isoallospirostan-l lot-ol-3 one acetate.

22; A new compound selected from the group consisting of 23 brominated 2-iodo-A -spirosten-1lot-01 3- V onecompoynds and esters thereof.

9 10' sisting of M-spirosten-l1a-ol-3-0ne compounds and esters 32. A -22-isospirostadien-3-1la-diol diacetate. thereof. 33. A compound selected from the group consisting of 27. A -22-isospirosten-11a-o1-3-one. a 23 brominated A -spirosten-3 3,lla-diol compound and 28. A -22isospirosten-11a-o1-3-one acetate. esters thereof.

29. A 23 brominated A -spirostadien-3,lla-diol di- 5 34. 23-brorno-A -22-isospirosten-3 8,1la-diol.

acetate. 35. 23-bromo-A -22-isospirosten-3fl,1la-diol diacetate.

30. 23 bromo A -22 isospirostadien 3,11u-diol diacetate.

31. A diester of A -spirostadien-3Jla-diol.

No references cited. 

1. A PROCESS FOR THE PRODUCTION OF AN 11-MONO ESTER OF AN ALLOSPIROSTAN-11A-OL-3-ONE WHICH COMPRISES TREATING A CORRESPONDING DIESTER OF AN ALLOSPIROSTAN-3B,11A-DIOL WITH A MOLAR EQUIVALENT OF A MILD SAPONIFYING AGENT TO PRODUCE THE CORRESPONDING 11-MONO ESTER AND OXIDIZING SAID 11-MONO ESTER WITH AN OXIDIZING AGENT SELECTEF FROM THE GROUP CONSISTING OF CHROMIC ACID, N-BROMOACETAMIDE AND AN ALUMINUM ALKOXIDE IN THE PRESENSCE OF A HYDROGEN ACCEPTOR.
 7. A PROCESS FOR THE PRODUCTION OF A 23 BROMINATED ESTER OF $4-SPRIROSTEN-11A-OL-3-ONE, WHICH COMPRISES TREATING A CORRESPONDING 23 BROMINATED ESTER OF 2-IODO-$4SPIROSTEN-11A-OL-3-ONE WITH A REDUCING AGENT SELECTED FROM THE CLASS CONSISTING OF CHROMOUS CHLORIDE, A TERTIARY AMINE AND SODIUM SULFITE. 